targeted (e.g. sunitinib,trastuzumab) therapies seldom cause myelosuppression.
INFECTION
Infection is a common and life-threatening complication of chemotherapy. It is often acquired from the patient’s own gas- tro-intestinal tract flora. Effective isolation is achieved in pur- pose-built laminar-airflow units, but this does not solve the problem of the patient’s own bacterial flora. Classical signs of infection – other than pyrexia – are often absent in neutropenic patients, and constant vigilance is required to detect and treat septicaemia early. Broad-spectrum antibiotic treatment must be started empirically in febrile neutropenic patients before the results of blood and other cultures are available. Combination therapy with an aminoglycoside active against Pseudomonas and other Gram-negative organisms (e.g. tobramycin, netilmicin oramikacin) plus a broad-spectrum ureidopeni- cillin (e.g. piperacillin) may be used. Alternatively, monother- apy with a third- or fourth-generation cephalosporin active against β-lactamase-producing organisms (e.g. ceftazidime, cefotaximeorcefipime) can provide suitable empiric cover- age. Therapeutic decisions need to be guided by knowledge of local organisms, the patient’s previous antimicrobial therapy and culture results (see Chapter 43). Opportunistic infections with fungi or protozoa (e.g. Pneumocystis carinii) can occur;
details of the treatment for such infections are to be found in Chapters 43, 45 and 46.
ALOPECIA
Doxorubicin, ifosfamide, parenteral etoposide, camptothe- cins, anti-metabolites, vinca alkaloids and taxanes all com- monly cause alopecia. This may be ameliorated in the case of doxorubicinby cooling the scalp with, for example, ice-cooled water caps. Some hair loss occurs with many cytotoxic agents.
INFERTILITY AND TERATOGENESIS
Cytotoxic drugs predictably impair fertility and cause fetal abnormalities. Most women develop amenorrhoea if treated with cytotoxic drugs. However, many resume normal menstru- ation when treatment is stopped and pregnancy is then pos- sible, especially in younger women who are treated with lower total doses of cytotoxic drugs. In men, a full course of cytotoxic drugs usually produces azoospermia. Alkylating agents are particularly harmful. Recovery can occur after several years.
Sperm storage before chemotherapy can be considered for males who wish to have children in the future. Reproductively active men and women must be advised to use appropriate contraceptive measures during chemotherapy, as a reduction in fertility with these drugs is not universal and fetal malforma- tions could ensue. It is best to avoid conception for at least six months after completion of cytotoxic chemotherapy.
SECOND MALIGNANCY
Up to 3–10% of patients treated for Hodgkin’s disease (particu- larly those who received both chemotherapy and radiation therapy) develop a second malignancy, usually acute non- lymphocytic leukaemia. This malignancy is also approxi- mately 20 times more likely to develop in patients with ovarian carcinoma treated with alkylating agents with or without radiotherapy. This delayed treatment complication is likely to increase in prevalence as the number of patients who survive after successful cancer chemotherapy increases.
10 000 5000
500 1000
100 0 3 9 15 21 03 9 1521 27 33 39 45 51 57
(a) (b)
Partial recovery
Secondary fall
Polymorph count/mm3
Therapy Therapy
Figure 48.3:Patterns of bone marrow recovery following cytotoxic therapy: (a) rapid (17–21 days) and (b) delayed (initial fall 8–10 days, secondary nadir at 27–32 days, recovery 42–50 days) (after DE Bergasagel).
Key points
Adverse effects of cytotoxic chemotherapy
• Immediate effects:
– nausea and vomiting (e.g. cisplatin, cyclophosphamide);
– drug extravasation (e.g. vinca alkaloids, anthracyclines, e.g. doxorubicin).
• Delayed effects:
– bone marrow suppression – all drugs;
– infection;
– alopecia;
– drug-specific organ toxicities (e.g. skin and
pulmonary – bleomycin; cardiotoxicity – doxorubicin);
– psychiatric-cognitive morbidity;
– teratogenesis.
• Late effects:
– gonadal failure/dysfunction;
– leukaemogenesis/myelodysplasia;
– development of secondary cancer.
DRUGS USED IN CANCER CHEMOTHERAPY
These include the following:
1. alkylating agents;
2. antimetabolites;
372 CANCER CHEMOTHERAPY 3. DNA-binding agents;
4. topoisomerase inhibitors;
5. microtubular inhibitors (vinca alkaloids and taxanes);
6. molecularly targeted agents; small molecules and monoclonal antibodies;
7. hormones;
8. biological response modifiers.
ALKYLATING AGENTS
Alkylating agents are particularly effective when cells are dividing rapidly, but are not phase-specific. They combine with DNA and thus damage malignant and dividing normal cells (see Table 48.5). If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-resistance does not necessarily occur. The pharmacokinetic properties of the different drugs are probably important in this respect. For example, although most alkylating agents diffuse passively into cells, mustineis actively transported by some cells.
MUSTINE (MECHLORETHAMINE) Uses
Mustine is used in combination cytotoxic regimes (e.g. in refractory Hodgkin’s disease).
Mechanism of action
Mustineforms highly reactive ethyleneimine ions that alkyl- ate and cross-link guanine bases in DNA (Figure 48.4) and alkylate other macromolecules, including proteins.
Adverse effects
Adverse effects are listed in Table 48.5.
Pharmacokinetics
Mustineis given intravenously. The reactive ethyleneimine ion forms spontaneously due to cyclization in solution. The plasmat1/2is approximately 30 minutes.
Other oral agents in this class of nitrogen mustards include carmustine(BCNU) and lomustine(CCNU).
CYCLOPHOSPHAMIDE Uses
Cyclophosphamideis an oxazaphosphorine alkylating agent (ifosfamide is another). It is an inactive prodrug given orally or intravenously. Several combination cytotoxic regi- mens include cyclophosphamide. Very high marrow ablative
Table 48.5:Comparative pharmacology of classical alkylating agents
Drug Route of Nausea and Granulocytopenia Thrombocytopenia Special
administration vomiting toxicity
Mustine i.v. Tissue necrosis if extravasated
Cyclophosphamide Oral/i.v. Alopecia (10–20%)
Chemical cystitis (reduced by mesna) Mucosal ulceration
Impaired water excretion Interstitial pulmonary fibrosis
Ifosfamide i.v. Chemical cystitis (reduced by mesna)
Alopecia
Chlorambucil Oral Bone marrow suppression
Melphalan Oral 0 Chemical cystitis (very rare)
Busulfan Oral 0 Skin pigmentation
Interstitial pulmonary fibrosis Amenorrhoea
Gynaecomastia (rare) T
T
T
A A T
A
C C
C C
C C
G G
G G
G G
G Alkylating
agent
DNA
i.e.
A
Figure 48.4:Mechanism of intramolecular bridging of DNA by alkylating agents. A, adenine; C, cytosine; G, guanine;
T, thymidine.
DRUGSUSED INCANCERCHEMOTHERAPY 373 doses are used to prepare patients with acute leukaemia or
aplastic anaemia for allogeneic bone marrow transplantation.
Cyclophosphamide is highly effective in treating various lymphomas, leukaemias and myeloma, but also has some use in other solid tumours. It is an effective immunosuppressant (Chapter 50).
Adverse effects
Adverse effects are listed in Table 48.5.
Pharmacokinetics
Cyclophosphamideundergoes metabolic activation in the liver via CYP2B6 and chronic use autoinduces the metabolic acti- vation to cytotoxic alkylating metabolites, the most potent of which is the short-lived phosphoramide mustard. Absorption from the gastro-intestinal tract is excellent (essentially 100%
bioavailabilty). Cyclophosphamide and its metabolites are excreted in the urine. Renal excretion of one of its metabolites, acrolein, causes the haemorrhagic cystitis that accompanies high-dose therapy.
MESNA (UROPROTECTION AGENT) Use
Mesna(2-mercaptoethane sulphonate) is solely used to protect the urinary tract against the urotoxic metabolites of cyclophos- phamide and ifosfamide. Mesna is given by intravenous injection or by mouth. Because mesnais excreted more rapidly (t1/2is 30 minutes) than cyclophosphamideandifosfamide, it is important that it is given at the initiation of treatment, and that the dosing interval is no more than four hours. The mesna dose and schedule vary with the dose of cyclophosphamideor ifosfamide. Urine is monitored for volume, proteinuria and haematuria. The side effects of mesnainclude headache, som- nolence and rarely rashes.
Mechanism of action
Mesnaprotects the uro-epithelium by reacting with acrolein in the renal tubule to form a stable, non-toxic thioether.
OTHER ALKYLATING AGENTS
PROCARBAZINE Uses
Procarbazine, a hydrazine, is a component of combina- tion therapy for Hodgkin’s disease and brain tumours.
Procarbazineis given daily by mouth. The other agent in this class is dacarbazine.
Mechanism of action
Procarbazineis activated in the liver by CYP450 enzymes to reactive azoxy compounds that alkylate DNA. In addition, it methylates DNA and inhibits DNA and protein synthesis.
Adverse effects
These include the following:
• dose-related haematopoietic suppression, leukopenia and thrombocytopenia at 10–14 days after treatment;
• nausea and vomiting.
Pharmacokinetics
Procarbazine is well absorbed. The plasma t1/2 is approxi- mately ten minutes. Procarbazineand its metabolites penetrate the blood–brain barrier. It is converted to active metabolites in the liver (see above); these are excreted by the kidneys.
Drug interactions
Procarbazine blocks aldehyde dehydrogenase (for compari- son see disulfiram, Chapter 53) and consequently causes flushing and tachycardia if ethanolis taken concomitantly. It is also a weak monoamine oxidase inhibitor and may precipi- tate a hypertensive crisis with tyramine-containing foods (Chapter 20).
PLATINUM COMPOUNDS CISPLATIN
Uses
Cisplatinis an inorganic platinum (II) co-ordination complex in which two amine (NH3) and two chlorine ligands occupy cis positions (the trans compound is inactive). Cisplatin is markedly effective for testicular malignancies and several other solid tumours, including carcinoma of the ovary, lung, head and neck, and bladder may also respond well. Cisplatin is given intravenously in combination with other cytotoxic agents. Because of the efficacy of platinum compounds and the toxicity of cisplatin, there has been a search for less toxic analogues, yielding carboplatinandoxaliplatin. The compara- tive pharmacology of carboplatinandoxaliplatinis summar- ized in Table 48.6.
Mechanism of action
Platinum compound cytotoxicity results from selective inhib- ition of tumour DNA synthesis by the formation of intra- and inter-strand cross-links at guanine residues in the nucleic acid backbone. This unwinds and shortens the DNA helix.
Adverse effects
These include the following:
• severe nausea and vomiting;
• nephrotoxicity (especially cisplatin) which is dose-related and dose-limiting. Prehydration and fluid diuresis reduce the immediate effects, but cumulative and permanent damage still occurs;
• hypomagnesaemia and hypokalaemia;
• ototoxicity develops in up to 30% of patients: audiometry should be carried out before, during and after treatment;
374 CANCER CHEMOTHERAPY
• myelosuppression – usually thrombocytopenia;
• nervous system effects – cerebellar syndrome, peripheral neuropathy.
Pharmacokinetics
Cisplatinrequires the replacement of the two chloride atoms with water (‘aquation’) to become active. This process takes approximately 2.5 hours. Plasma disappearance of cisplatinis multiphasic and traces of platinum are detectable in urine months after treatment.
Drug interactions
Additive nephrotoxicity and ototoxicity occurs with amino- glycosides or amphotericin.
ANTIMETABOLITES
Antimetabolites are structural analogues of, and compete with, endogenous nucleic acid precursors. Unfortunately, the pathways blocked by antimetabolites are not specific to neo- plastic cells. Thus, their selectivity for malignant cells is only partial. They act in the S-phase of the cell cycle.
ANTIFOLATE ANALOGUES METHOTREXATE
Uses
Methotrexate is curative for choriocarcinoma, also induces remission in acute lymphocytic leukaemia and is often active in breast cancer, osteogenic sarcoma and head and neck tumours.
Methotrexateis also an immunosuppressant (Chapters 26 and 50) and is used to inhibit cellular proliferation in severe psoria- sis (Chapter 51). There are several different dosage schedules, several of which require co-administration of folinic acid (see Figure 48.5).
Mechanism of action
Folic acid is required in the synthesis of thymidylate (a pyrimidine) and of purine nucleotides and thus for DNA syn- thesis (Figure 48.5). Methotrexateis a very slowly reversible competitive inhibitor of dihydrofolate reductase (DHFR). The affinity of DHFR for methotrexateis 100 000 times greater than that for dihydrofolate. Thus, methotrexate prevents nucleic acid synthesis and causes cell death. Folinic acid circumvents this biosynthetic block and thus non-competitively antagonizes the effect of methotrexate.
Determinants of methotrexate toxicity These consist of:
• a critical extracellular concentration for each target organ;
• a critical duration of exposure that varies for each organ.
For bone marrow and gut, the critical plasma concentration is 2108Mand the time factor is approximately 42 hours.
Both factors must be exceeded for toxicity to occur in these organs. The severity of toxicity is proportional to the length of time for which the critical concentration is exceeded and is independent of the amount by which it is exceeded.
Folinic acid rescue bypasses the dihydrofolate reductase blockade and minimizes methotrexate toxicity. Some malig- nant cells are less able to take up folinic acid than normal cells, thus introducing a degree of selectivity. Rescue is commenced 24 hours after methotrexateadministration and continued until the plasma methotrexateconcentration falls below 5108M. Monitoring of the plasma methotrexate concentrations has improved the safe use of this drug and allows identification of patients at high risk of toxicity. If a patient develops severe tox- icity with protracted elevation of methotrexateconcentrations, methotrexatemetabolism can be rapidly increased by adminis- tering an inactivating enzyme, namely carboxypeptidase-G2 (not routinely available in the UK), when methotrexateconcen- trations exceed 1107M.
Table 48.6:Comparative pharmacology of some platinum compounds
Drug Standard dosing regimen Side effects Pharmacokinetics Additional comments Carboplatin (CBP) i.v. dose is calculated based Like cisplatin, but less Activation slower than Anti-tumour spectrum
on the desired AUC by the vomiting and cisplatin t1/22–3 h, 60–70% similar to that of cisplatin Calvert formula nephrotoxicity. Low excreted in the urine in
potential for ototoxicity first 24 h and neuropathy
Oxaliplatin i.v. administration. Mild bone marrow Biotransformed in blood. Third generation
Bulky DACH carrier ligand. suppression. Little Renal and tissue platinum analogue. Activity Unlike cisplatin or carboplatin nephro- or ototoxicity, elimination. Good tissue profile differs from cisplatin.
cf. cisplatin but cold-induced distribution due to DACH Ovarian, colorectal,
neurosensory toxicity pancreatic cancer, and
mesothelioma CDDP, cisplatin; DACH, diaminocyclohexane.
DRUGSUSED INCANCERCHEMOTHERAPY 375
Adverse effects
These include the following:
• myelosuppression;
• nausea and vomiting;
• stomatitis;
• diarrhoea;
• cirrhosis – chronic low-dose administration (as for psoriasis) can cause chronic active hepatitis and cirrhosis, interstitial pneumonitis and osteoporosis;
• renal dysfunction and acute vasculitis (after high-dose treatment);
• intrathecal administration also causes special problems, including convulsions, and chemical arachnoiditis leading to paraplegia, cerebellar dysfunction and cranial nerve palsies and a chronic demyelinating encephalitis.
Renal insufficiency reduces methotrexateelimination and monitoring plasma methotrexate concentration is essential under these circumstances. Acute renal failure can be caused by tubular obstruction with crystals of methotrexate. Diuresis (3 L/day) with alkalinization (pH 7 ) of the urine using intravenous sodium bicarbonate reduces nephrotoxicity.
Renal damage is caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the tubules, and these weak acids are more water soluble at an alkaline pH, which favours their charged form (Chapter 6).
Pharmacokinetics
Methotrexateabsorption from the gut occurs via a saturable transport process, large doses being incompletely absorbed. It is also administered intravenously or intrathecally. After intra- venous injection, methotrexateplasma concentrations decline in a triphasic manner, with prolonged terminal elimination due to enterohepatic circulation. This terminal phase is impor- tant because toxicity is related to the plasma concentrations during this phase, as well as to the peak methotrexateconcen- tration. Alterations in albumin binding affect the pharmacoki- netics of the drug. Methotrexate penetrates transcellular
water (e.g. the plasma: CSF ratio is approximately 30:1) slowly by passive diffusion. About 80–95% of a dose of methotrexate is renally excreted (by filtration and active tubular secretion) as unchanged drug or metabolites. It is partly metabolized by the gut flora during enterohepatic circulation.
7-Hydroxymethotrexate is produced in the liver and is phar- macologically inactive but much less soluble than methotrex- ate, and so contributes to renal toxicity by precipitation and crystalluria.
Drug interactions
• Probenecid, sulphonamides, salicylates and other NSAIDs increase methotrexatetoxicity by competing for renal tubular secretion, while simultaneously displacing it from plasma albumin. Other weak acids including furosemide and high-dose vitamin C compete for renal secretion.
• Gentamicinandcisplatinincrease the toxicity of methotrexateby compromising renal excretion.
PYRIMIDINE ANTIMETABOLITES 5-FLUOROURACIL
Uses
5-Fluorouracil (5-FU) is used to treat solid tumours of the breast, ovary, oesophagus, colon and skin. 5-Fluorouracil is administered by intravenous injection. Dose reduction is required for hepatic dysfunction or in patients with a genetic deficiency of dihydropyridine dehydrogenase.
Mechanism of action
5-Fluorouracilis a prodrug that is activated by anabolic phos- phorylation (Figure 48.6) to form:
• 5-fluorouridine monophosphate, which is incorporated into RNA, inhibiting its function and its polyadenylation;
• 5-fluorodeoxyuridylate, which binds strongly to thymidylate synthetase and inhibits DNA synthesis.
Incorporation of 5-fluorouracilitself into DNA causes mis- matching and faulty mRNA transcripts.
Methotrexate
Dihydrofolate reductase
Dihydrofolate Tetrahydrofolate
Leucovorin (folinic acid or N5-formyl tetrahydrofolate)
N5,10-methenylene tetrahydrofolate
Uridylate Thymidylate
DNA Purines Precursors N10-formyl
tetrahydrofolate Inhibits
N5,10-methenyl tetrahydrofolate
Figure 48.5:Folate metabolism: effects of methotrexate and leucovorin (folinic acid).
376 CANCER CHEMOTHERAPY
Adverse effects
• Oral ulceration and diarrhoea is an adverse event in approximately 20% of patients.
• Bone marrow suppression – megaloblastic anaemia usually occurs about 14 days after starting treatment.
• Cerebellar ataxia (2% incidence) is attributed to fluorocitrate, a neurotoxic metabolite that inhibits the Krebs cycle by lethal synthesis.
• Patients with dihydropyridine dehydrogenase deficiency (enzyme activity 5% of normal) have an increased risk of severe mucositis/haematologic suppression.
Pharmacokinetics
5-Fluorouracilis given intravenously because it is variably absorbed from the gut due to high hepatic first-pass metab- olism. Deactivation occurs primarily in the liver, where it is reduced to inactive products that are excreted in the urine.
Only 20% is excreted unchanged in the urine.
Capecitabine, an oral prodrug, is de-esterified and deami- nated to yield high concentrations of 5-deoxy fluorodeoxyuri- dine (5-dFdU). 5-dFdU is then converted in the liver, peripheral tissues and tumour to produce 5-FU concentrations that are about 10% of the 5-dFdU concentrations. Capecitabineis used to treat breast, lung and colorectal cancer and has the same tox- icity profile as 5-FU.
PURINE ANTIMETABOLITES 6-MERCAPTOPURINE Uses
6-Mercaptopurine(6-MP) is a purine antimetabolite. It is effect- ive as part of combination therapy for acute leukaemias. It is also an immunosuppressant (Chapter 50). Other purine
antimetabolites that are used clinically include tioguanine, fludarabine and 2-chlorodeoxyadenosine [cladrabine] (see Table 48.7).
Mechanism of action
6-MPrequires transformation by intracellular enzymes to 6- thioguanine which inhibits purine synthesis.
Adverse effects
These include the following:
• bone marrow suppression (macrocytosis, leukopenia and thrombocytopenia);
• mucositis;
• nausea, vomiting and diarrhoea with high doses;
• reversible cholestatic jaundice.
Pharma.cokinetics
Only approximately 15% of 6-MP is absorbed when given orally. Thiopurine-S-methyltransferase (TPMT) catalyses the S-methylation and deactivation of thiopurines (6-MP,azathio- prine and 6-thioguanine). TPMT is deficient in one in 300 white Europeans. TPMT-deficient individuals are at very high risk of haematopoietic suppression with standard doses of 6- MPbecause of the accumulation of thiopurines. Pretreatment assessment is currently the only pharmacogenetic test in rou- tine use (Chapter 14). Xanthine oxidase also contributes appre- ciably to inactivation of thiopurine drugs. Approximately 20%
of an intravenous dose of 6-MPis excreted in the urine within six hours, thus renal dysfunction enhances toxicity.
Drug interactions
Allopurinolinhibits xanthine oxidase (Chapter 26). The usual dose of 6-MPshould be reduced by 75% to avoid toxicity in Uridine phosphorylase
5-FU 5-Fluorouridine
Uridine kinase
5-Fluorouridylate Phosphoribosyl
transferase Hepatic
dihydrouracil dehydrogenase
Dihydro 5-FU
Catabolism RNA
DNA 5-Fluorouridine
diphosphate
5-Fluorodeoxyuridylate Inhibits
Uridine monophosphate
Thymidylate synthetase
Thymidine monophosphate
Figure 48.6:Metabolism and activation of 5-fluorouracil (5-FU).
DRUGSUSED INCANCERCHEMOTHERAPY 377
patients who are concurrently taking allopurinol. This is important because allopurinolpretreatment is used to reduce the risk of acute uric acid nephropathy due to rapid tumour lysis syndrome in patients with leukaemia.
ANTIBIOTICS
Several antibiotics (e.g. anthracyclines, anthracenediones – mitoxantrone) are clinically useful antineoplastic agents (see Table 48.8).
ANTHRACYCLINES
Doxorubicin and daunorubicin are the most widely used drugs in this group, but newer analogues (e.g. epirubicin, idarubicin) have reduced hepatic and cardiac toxicity, and idarubicinmay be administered orally.
DOXORUBICIN Uses
Doxorubicin is a red antibiotic produced by Streptomyces peucetius. It is the most widely used drug of the anthracycline group, with proven activity in acute leukaemia, lymphomas, sarcomas and a wide range of carcinomas. Liposomal formu- lations of doxorubicinare available.
Mechanism of action
Cytotoxic actions of anthracyclines lead to apoptosis, and include:
• intercalation between adjacent base pairs in DNA, leading to fragmentation of DNA and inhibition of DNA repair, enhanced by DNA topoisomerase II inhibition;
• membrane binding alters membrane function and contributes to cardiotoxicity;
• free-radical formation also causes cardiotoxicity.
Adverse effects
These include the following:
• cardiotoxicity – acute and chronic (see below);
• bone marrow suppression with neutropenia and thrombocytopenia;
• alopecia – may be mitigated by scalp cooling;
• nausea and vomiting;
• ‘radiation recall’ – anthracyclines exacerbate or reactivate radiation dermatitis or pneumonitis;
• extravasation causes severe tissue necrosis.
Anthracycline cardiotoxicity
• Acute: this occurs shortly after administration, with the development of various dysrhythmias that are occasionally life-threatening (e.g. ventricular tachycardia, heart block).
These acute effects do not predict chronic toxicity.
Table 48.7:Summary of clinical pharmacology properties of common antimetabolites
Drug Use Mechanism Side effects Additional comments
Cytosine arabinoside Acute leukaemia (AML) Inhibits pyrimidine Nausea and vomiting, Short half-life, (cytarabine) synthesis and in its bone marrow suppression, continuous infusions or
triphosphate form mucositis, cerebellar daily doses intravenously
inhibits DNA syndrome or subcutaneously, dose
polymerase reduced in renal
dysfunction
Fludarabine Chronic lymphocytic Inhibits purine Myelosuppression, pulmonary Daily i.v. dosing, reduce leukaemia (CLL) synthesis toxicity, CNS toxicity dose in renal failure
2-Chlorodeoxy CLL and acute Converted to Severe neutropenia i.v. infusion
2-chlorodeoxy leukaemia (ANLL) triphosphate and
adenosine inhibits purine
(cladribine) synthesis
Gemcitabine Pancreatic and lung cancer Cytidine analogue – Haematopoietic suppression, i.v. infusion, inactivated triphosphate form mucositis, rashes by cytidine deaminase,
incorporated into DNA, active throughout the
blocks DNA synthesis cell cycle, dose reduced in
renal dysfunction Hydroxyurea CML and myelo- Inhibits ribonucleotide Neutropenia, nausea, Oral dosing, short proliferative disorders reductase, affecting skin reactions half-life, rapidly
DNA and RNA synthesis reversible toxicity